As the AIDS pandemic continues, the emergence of HIV variants that are drug resistant is a therapeutic challenge. The nine FDA-approved HIV-1 protease inhibitors are currently the most potent of the anti-viral drugs in the treatment of HIV infected patients. All of these inhibitors were the results of structure based drug design. Yet variants of HIV protease have evolved which are resistant to one or more of these drugs. Even within a single patient an ensemble of different viruses and therefore proteases exist. The challenge for the community is to develop HIV-1 protease inhibitors that are robust and therefore less vulnerable to drug resistance. This is a multi-disciplinary challenge, as two key thrusts must be addressed - both the underlying mechanisms of resistance must be elucidated and new strategies for identifying robust inhibitors against resistance must be developed. This project aims to address this challenge by a comprehensive approach that integrates clinical data, structural biology and biophysical chemistry, medical informatics and biostatistics, biochemistry and molecular virology, computational chemistry and computer-aided design, and synthetic and medicinal chemistry. With this integrated program we plan to address two global research objectives: 1. Elucidate the role of compensatory mutations in HIV-1 protease in conferring drug resistance 2. Develop new HIV-1 protease inhibitors that are more robust against drug resistance. Through this integrated approach our goal is to attain a better understanding of inhibitor recognition and to develop new methodologies for designing inhibitors against quickly evolving targets that have a propensity for acquiring drug resistance.